1. Technical Field
The present disclosure relates generally to methods for enhancing the specific immune response to an immunogen by immunizing a subject with at least two compositions to induce humoral and cellular immune responses to the immunogen.
2. Description of the Related Art
The immune system of a host provides the means for quickly and specifically mounting a protective response to pathogenic microorganisms and also for contributing to rejection of malignant tumors. Immune responses have been generally described as including humoral responses, in which antibodies specific for antigens are produced by differentiated B lymphocytes, and cell mediated responses, in which various types of T lymphocytes eliminate antigens by a variety of mechanisms. For example, CD4 (also called CD4+) helper T cells that are capable of recognizing specific antigens may respond by releasing soluble mediators such as cytokines to recruit additional cells of the immune system to participate in an immune response. CD8 (also called CD8+) cytotoxic T cells are also capable of recognizing specific antigens and may bind to and destroy or damage an antigen-bearing cell or particle. In particular, cell mediated immune responses that include a cytotoxic T lymphocyte (CTL) response can be important for elimination of tumor cells and cells infected by a microorganism, such as virus, bacteria, or parasite.
Cancer includes a broad range of diseases and affects approximately one in four individuals worldwide. A CTL response is a key feature of effective cancer vaccines; effective CD4 T cell help is also likely to play a critical role in productive CD8 T cell activation and thus provide clinical benefit. The autologous dendritic cell (DC)-based vaccine Sipuleucel-T (PROVENGE®) was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic, castrate-resistant prostate cancer though the survival benefit associated with this treatment is a modest 4.1 months, leaving significant need for improvement (see, e.g., Kantoff, et al., New Engl. J. Med. 363(5):411 (2010)). The poxvirus-vector based vaccine ProstVac® VF also shows a significant survival benefit in Phase II (see, e.g., Kantoff, et al., J. Clin. Oncol. 28(7):1099 (2010)). Active immune therapies such as Sipuleucel-T and ProstVac® VF have generally been better tolerated than the chemotherapeutic regimens that comprise the current standard of care for castrate-resistant disease (see, e.g., Petrylak, et al., N. Engl. J. Med. 351(15):1513 (2004); Sylwester, et al., J. Exp. Med. 202(5):673 (2005)). These clinical successes demonstrate that the immune response can be harnessed in a cancer setting to provide improved patient outcomes and extended survival.
With respect to microbial infections, malaria, tuberculosis, HIV-AIDS and other viral infections such as Herpes Simplex Virus (HSV) infections (the leading cause of genital ulcers worldwide) continue to contribute to global health concerns. HSV-2 prevalence is increasing at an alarming rate across the globe (see, e.g., Corey et al., J. Acquir. Immune Defic. Syndr. 35:435 (2004)). In the United States, the overall HSV-2 seroprevalence rate exceeds 20%, and in developing nations HSV-2 prevalence is estimated between 30% and 50%. In addition to the profound burden of HSV-2 infection in adults, the incidence of neonatal HSV-2 infection is increasing. Even when treated, neonatal encephalitis from HSV-2 infection has a mortality >15%, and the neurological morbidity among HSV-2 infected infants is an additional 30 to 50% of surviving cases. Concomitant with the HSV-2 epidemic is a stark realization that HSV-2 infection substantially increases the risk for HIV-1 acquisition and transmission. Data from Africa show that HSV-2 infection can increase the risk for HIV transmission by as much as 7-fold and that as many as half of newly acquired HIV cases are directly attributed to HSV-2 infection (see, e.g., Abu-Raddad et al., PLoS ONE 3(5):e2230 (2008)). Overall, the relative risk of HIV acquisition increases more than 2-fold in HSV-2-infected individuals.
The increasing prevalence of HSV-2 in the adult and pediatric populations persists despite the widespread use of pharmacological intervention. Antiviral medication given at high doses early in infection can reduce HSV transmission, but this does not prevent latent infection (see, e.g., Corey et al., Sex Transm. Dis. 12:215 (1985)). In a recent study, continuous suppressive administration with Valacyclovir reduced HSV transmission by less than 50% despite early intervention (see, e.g., Corey et al., N. Engl. J. Med. 350:11 (2004)). Alternatives to antiviral drugs, such as topical microbicides are unproven clinically. For these reasons, many leading authorities believe that vaccination is essential for diminishing the health impact of HSV-2 disease.
A need exists for vaccines, including improved vaccines, against infectious disease microorganisms, such as Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus, malaria, antibiotic resistant bacteria, for which inducing a robust humoral and/or cell-mediated response is important for successful prevention and treatment of infection. In addition, considerable potential and need exists for improved cancer vaccine potency.